Development and Characterizations of Pullulan and Maltodextrin-Based Oral Fast-Dissolving Films Employing a Box-Behnken Experimental Design.

Migraine is a neurological disorder characterized by severe headaches, visual aversions, auditory, and olfactory disorders, accompanied by nausea and vomiting. Zolmitriptan (ZMT®) is a potent 5HT1B/1D serotonin receptor agonist frequently used for the treatment of migraine. It has erratic absorption from the gastrointestinal tract (GIT), but its oral bioavailability is low (40-45%) due to the hepatic metabolism. This makes it an ideal candidate for oral fast dissolving formulations. Hence, the current study was undertaken to design and develop oral fast-dissolving films (OFDFs) containing ZMT for migraine treatment. The OFDFs were formulated by the solvent casting method (SCM) using Pullulan (PU) and maltodextrin (MDX) as film-forming agents and propylene glycol (PG) as a plasticizer. The strategy was designed using Box-Behnken experimental design considering the proportion of PU:MDX and percentage of PG as independent variables. The effectiveness of the OFDF's was measured based on the following responses: drug release at five min, disintegration time (D-time), and tensile strength (TS). The influence of formulation factors, including percent elongation (%E), thickness, water content, moisture absorption, and folding endurance on ZMT-OFDFs, were also studied. The results showed a successful fabrication of stable ZMT-OFDFs, with surface uniformity and amorphous shape of ZMT in fabricated films. The optimized formulation showed a remarkable rapid dissolution, over 90% within the first 5 min, a fast D-time of 18 s, and excellent mechanical characteristics. Improved maximum plasma concentration (C max) and area under the curve (AUC 0-t) in animals (rats) treated with ZMT-OFDFs compared to those treated with an intra-gastric (i-g) suspension of ZMT were also observed. Copolymer OFDFs with ZMT is an exciting proposition with great potential for the treatment of migraine headache. This study offers a promising strategy for developing ZMT-OFDFs using SCM. ZMT-OFDFs showed remarkable rapid dissolution and fast D-time, which might endeavor ZMT-OFDFs as an auspicious alternative approach to improve patient compliance and shorten the onset time of ZMT in migraine treatment.

Polyplexes by Polymerized Dequalinium and Bifunctional Aptamer for Mitochondrial Targeting Drug Release to Overcome Drug Resistance.

Drug resistance is one of the major obstacles to the success of cancer chemotherapy. Mitochondrial targeting drugs are increasingly thought to be able to eradicate resistant cancer cells. However, immature drug release outside mitochondria and the absence of multifunctional targeting carriers against tumor mitochondria greatly limit the corresponding therapeutic benefits. Here, we synthesized polymerized dequalinium by integrating dequalinium, lysine, and poly(ethylene glycol) for mitochondrial targeting. The polymerized dequalinium exhibited lower cytotoxicity and stronger gene condensing ability than free dequalinium. We designed AS1411-ATP fusion aptamer to load doxorubicin (DOX) for both tumor targeting and ATP-responsive DOX release. The polyplexes by polymerized dequalinium and bifunctional aptamer can target tumor cells via AS1411 and show improved stability, mitochondrial targeting, DOX release in response to mitochondrial ATP, and enhanced apoptosis-inducing effect on DOX-resistant MCF-7/DOX cells. The present study highlights a promising application of the polyplexes in reversing drug resistance in tumor cells via tumor mitochondrial targeting drug release.

LRP1-upregulated nanoparticles for efficiently conquering the blood-brain barrier and targetedly suppressing multifocal and infiltrative brain metastases.

Brain metastases present mostly multifocal, infiltrative and co-opting growth with the blood-brain barrier (BBB) remaining intact. The BBB, as the barrier of drug delivery to such lesions, is the major cause of the failure of systemic drug therapy and needs to be conquered. Angiopep-2 ligates the low density lipoprotein receptor related protein 1 (LRP1) on brain microvascular endothelial cells (BMECs) to drive transcytosis for BBB crossing. However, besides tight junction, low transcytosis is increasingly deemed to be a crucial factor in restricting BBB permeability. Herein, it is reported that statins-loaded Angiopep-2-anchored nanoparticles (S@A-NPs) can raise LRP1 expression to surmount the low transcytosis of BBB. We demonstrate that S@A-NPs can selectively heighten LRP1 expression on both BMECs and brain metastatic tumor cells, efficiently and self-promotingly penetrate through the BBB and target brain metastases through Angiopep-2 mediated endocytosis and statins induced LRP1 up-regulation. The systemic administration of S@A-NPs loaded with doxorubicin (S@A-NPs/DOX) observably lengthens median survival of mice bearing brain metastases. Due to the efficient BBB passing and brain metastasis targeting, S@A-NPs/DOX may serve as a potential approach for clinical management of brain metastases.

Enantioselective Construction of Tetrahydroquinolin-5-one-Based Spirooxindole Scaffold via an Organocatalytic Asymmetric Multicomponent [3 + 3] Cyclization.

The first catalytic enantioselective construction of biologically important tetrahydroquinolin-5-one-based spirooxindole has been developed via a chiral cinchona alkaloid catalyzed asymmetric three-component [3 + 3] cyclization of cyclic enaminone, isatin, and malononitrile, which afforded a series of tetrahydroquinolin-5-one-based spirooxindoles in high yields and with excellent enantioselectivities (up to 99% yield, 97:3 er). This reaction could be applicable to large-scale synthesis of enantioenriched tetrahydroquinolin-5-one-based spirooxindoles. This synthetic methodology will not only provide a unique approach for the construction of chiral tetrahydroquinolin-5-one-based spirooxindole scaffolds but also increase our understanding of catalytic enantioselective multicomponent reactions.

Diastereo- and Enantioselective Construction of the Hexahydrocoumarin Scaffold via an Organocatalytic Asymmetric [3 + 3] Cyclization.

The first catalytic asymmetric construction of the biologically important hexahydrocoumarin scaffold has been established, which takes advantage of chiral thiourea-tertiary amine-catalyzed enantioselective transformations. Besides, this reaction also realized the first catalytic asymmetric [3 + 3] cyclization of 4-arylidene-2-aryloxazol-5(4H)-ones with cyclohexane-1,3-diones, which afforded structurally diverse 3-aminohexahydrocoumarin derivatives in excellent diastereoselectivities and high enantioselectivities (all >95:5 dr, up to 96:4 er). The investigation on the activation mode suggested that the chiral thiourea-tertiary amine catalyst simultaneously activated the two substrates via hydrogen-bonding interaction. Moreover, this reaction could be applied to a large scale synthesis of enantioenriched hexahydrocoumarin. This approach will not only provide an efficient method for the construction of the chiral hexahydrocoumarin scaffold but also enrich the research areas of asymmetric organocatalysis and catalytic enantioselective [3 + 3] cyclizations.

Merging Chiral Brønsted Acid/Base Catalysis: An Enantioselective [4 + 2] Cycloaddition of o-Hydroxystyrenes with Azlactones.

An enantioselective [4 + 2] cycloaddition of o-hydroxylstyrenes with azlactones has been established by merging chiral Brønsted acid (chiral phosphoric acid) and base (chiral guanidine) catalysis, which constructed a biologically important dihydrocoumarin scaffold in an efficient and enantioselective style (up to 99% yield, 96:4 er). This approach has not only realized the successful application of o-hydroxylstyrenes as oxa-diene precursors in catalytic asymmetric cycloadditions but also established a new cooperative catalytic system of chiral phosphoric acid and chiral guanidine.

Enantioselective construction of a 2,2'-bisindolylmethane scaffold via catalytic asymmetric reactions of 2-indolylmethanols with 3-alkylindoles.

A chiral phosphoric acid-catalyzed asymmetric reaction of 2-indolylmethanols with 3-alkylindoles has been established, which constructed a biologically important 2,2'-bisindolylmethane scaffold in high yields and good enantioselectivities (up to 98% yield, 94:6 er). This protocol not only provides an efficient method for constructing a 2,2'-bisindolylmethane framework in an enantioselective form, but also promotes the development of 2-indolylmethanol-involved catalytic asymmetric transformations.